Influenza or people typically prefer to as “flu” causes the infection of the throat, nose, and lungs that is similar to a common cold. Coughing and sneezing are ways that this disease transmits different type of virus through the air. Each year during the flu season that starts from October to March, about 5 to 20 percent of Americans are affected by the flu [1]. It is easier for children to spread the virus around than adults, which result in two to three times of higher chance for children to get the flu. The seasonal outbreaks of flu turn into an epidemic because of how widely it spreads out in communities. Before mutation occurred, the flu virus appears only in wild aquatic birds, but eventually the flu begins to spread into domesticated animals like poultry and swine. The exchange of genes in virus occurs when both avian and human flu are infecting the pig at the same. As a result, interaction between farm animal with human in farm setting causes the transmission of the flu to human. The severity of the influenza is depending on the avian protein’s combinations. The flu is more susceptible for children, especially five years of age or younger than adults because of the daily interaction in classroom like sharing a pencil. It is possible for people to discover that they have the flu after they pass it to someone else. Also, people with a weak immune system can be more easily affected by the influenza virus and once infected they are more likely to infect people for a longer period of time than the healthy adults, who can only infect for up to one week. Wide range symptoms of flu include a fever, sore throat, extreme tiredness, hacking cough, vomiting and headache and body aches. People usually get the flu for about a week and after that is lingering cough.
TARGET INFORMATION:
Figure 1. political cartoon on flu virus
Nonstructural protein 1 (NS1) with a molecular weight of about 26 kDA is 230 – 237 amino acid in length. It is found everywhere in the cytoplasm and nucleus in the lung cell. In the cytoplasm of oocytes (germ cell) is where NS1 concentrated. On the other hand in normally infected cells, concentration of NS1 is in the nucleolus [2]. This protein is important in the virus replication. Recognition of cleavage and polyadenylation specificity factor 30 causes the NS1 to interfere with RNA processing that inhibits IFN-b mRNA. In the host, NS1 blocks the normal immune response and inactivates the interferon (IFN) response, which is responsible for detecting pathogens such as bacteria and viruses in the body [3]. The pleiotropic effects of NS1 are causing the interaction with many different infected cells’ proteins and lead to different steps in cell metabolic pathway to be affected. Specific cellular proteins trigger molecular mechanisms of this protein. In gene expression, NS1 protein has impact in many of the steps. The steps in the process included poly(A) RNA nucleocytoplamic transport, splicing of pre-mRNA, and translation. (PKR) protein kinase will be activated because the double-stranded RNA is inactivated by the blocking of NS1[4]. This will result in the translation process that is regulated by PKR to be shut off and in turn affecting the cellular antiviral defense system.
Figure 2. Nonstructural protein 1 tertiary structure
DRUG INFORMATION:
Oseltamivir or oseltamivir phosphate has a trade name of Tamiflu with the CAS number of 104255-11-8. This drug is manufactured by Hoffman la Roche incorporation. The forms that this drug comes in are oral suspension and 30 and 45 mg capsules for children. The molecular formula of oseltamivir is C16H28N2O4 with the molecular weight of 312.4045 g/mol. This drug works as enzyme inhibitor, oseltamivir is developed as orally active inhibitor for neuraminidase. FDA approved Tamiflu in 1999 for use in patients of one year and older to prevent the flu. The sale of this drug is not profound at first, but as fear of avian flu pandemic thrived, this medication is widely acquired. Until 2016 Tamiflu is patent protected and is owned by Gilead. The most common detrimental side effects of oseltamivir include nausea, vomiting, diarrhea and abdominal pain. This drug has four phases of clinical trials. Oseltamivir is used to treat Type A and B influenza for patients of 2 weeks of age or older with flu symptoms of less than two days can be treated with this oral anti-viral drug.
Figure 3. Schematic figure of Oseltamivir
Over time virus can become resistance toward antiviral drug just like the case of amantadine and rimantadine that developed resistance for influenza A strain. In the host cell, the drug slow and prevent the influenza to cross the border into the cell. The prodrug of oseltamivir is ethyl ester so it needs to be ester hydrolyzed. At first when administered in an inactive form, oseltamivir has no sign of effective until it gets to the liver where the drug is put into action by hydrolyzed into its active form and the release of carboxylate from oseltamivir. This is the active metabolite that inhibits influenza A and B virus neuraminidase. On the surface of the influenza virus are neuraminidase coatings that allow the virus to invade the host cell membranes and then replicates into large number inside the host cell. Once the patient is affected with influenza virus, with oseltamivir the the surface of neuraminidase is bound and prevent the virus to leave the host cell. This will restrict the virus to replicate and multiply in number, which result in the body immune system a higher chance to kill the virus.
REFERENCES:
[1] http://www.niaid.nih.gov/topics/Flu/understandingFlu/Pages/overview.aspx/ (accessed January 29, 2014). [2] Engel, D. A., The influenza virus NS1 protein as a therapeutic target. Antiviral Research 2013, 99, (3), 409-16. [3] Davey, J.; Colman, A.; Dimmock, N. J., Locaton of influenza virus M, NP, and NS1 proteins in microinjected cells. J. gen. Virol. 1985, 66, (11), 2319-34. [4] Hale, B. G.; Randall, R.. E.; Dimmock, Ortin. J.; Jackson, D., The multifunctional NS1 protein of influenza A viruses. J. gen. Virol. 2008, 89, (10), 2359-76.
DISEASE/DRUG OF INTEREST:
MOTIVATION AND BACKGROUND:
Influenza or people typically prefer to as “flu” causes the infection of the throat, nose, and lungs that is similar to a common cold. Coughing and sneezing are ways that this disease transmits different type of virus through the air. Each year during the flu season that starts from October to March, about 5 to 20 percent of Americans are affected by the flu [1]. It is easier for children to spread the virus around than adults, which result in two to three times of higher chance for children to get the flu. The seasonal outbreaks of flu turn into an epidemic because of how widely it spreads out in communities. Before mutation occurred, the flu virus appears only in wild aquatic birds, but eventually the flu begins to spread into domesticated animals like poultry and swine. The exchange of genes in virus occurs when both avian and human flu are infecting the pig at the same. As a result, interaction between farm animal with human in farm setting causes the transmission of the flu to human. The severity of the influenza is depending on the avian protein’s combinations. The flu is more susceptible for children, especially five years of age or younger than adults because of the daily interaction in classroom like sharing a pencil. It is possible for people to discover that they have the flu after they pass it to someone else. Also, people with a weak immune system can be more easily affected by the influenza virus and once infected they are more likely to infect people for a longer period of time than the healthy adults, who can only infect for up to one week. Wide range symptoms of flu include a fever, sore throat, extreme tiredness, hacking cough, vomiting and headache and body aches. People usually get the flu for about a week and after that is lingering cough.
TARGET INFORMATION:
Nonstructural protein 1 (NS1) with a molecular weight of about 26 kDA is 230 – 237 amino acid in length. It is found everywhere in the cytoplasm and nucleus in the lung cell. In the cytoplasm of oocytes (germ cell) is where NS1 concentrated. On the other hand in normally infected cells, concentration of NS1 is in the nucleolus [2]. This protein is important in the virus replication. Recognition of cleavage and polyadenylation specificity factor 30 causes the NS1 to interfere with RNA processing that inhibits IFN-b mRNA. In the host, NS1 blocks the normal immune response and inactivates the interferon (IFN) response, which is responsible for detecting pathogens such as bacteria and viruses in the body [3]. The pleiotropic effects of NS1 are causing the interaction with many different infected cells’ proteins and lead to different steps in cell metabolic pathway to be affected. Specific cellular proteins trigger molecular mechanisms of this protein. In gene expression, NS1 protein has impact in many of the steps. The steps in the process included poly(A) RNA nucleocytoplamic transport, splicing of pre-mRNA, and translation. (PKR) protein kinase will be activated because the double-stranded RNA is inactivated by the blocking of NS1[4]. This will result in the translation process that is regulated by PKR to be shut off and in turn affecting the cellular antiviral defense system.
DRUG INFORMATION:
Oseltamivir or oseltamivir phosphate has a trade name of Tamiflu with the CAS number of 104255-11-8. This drug is manufactured by Hoffman la Roche incorporation. The forms that this drug comes in are oral suspension and 30 and 45 mg capsules for children. The molecular formula of oseltamivir is C16H28N2O4 with the molecular weight of 312.4045 g/mol. This drug works as enzyme inhibitor, oseltamivir is developed as orally active inhibitor for neuraminidase. FDA approved Tamiflu in 1999 for use in patients of one year and older to prevent the flu. The sale of this drug is not profound at first, but as fear of avian flu pandemic thrived, this medication is widely acquired. Until 2016 Tamiflu is patent protected and is owned by Gilead. The most common detrimental side effects of oseltamivir include nausea, vomiting, diarrhea and abdominal pain. This drug has four phases of clinical trials. Oseltamivir is used to treat Type A and B influenza for patients of 2 weeks of age or older with flu symptoms of less than two days can be treated with this oral anti-viral drug.Over time virus can become resistance toward antiviral drug just like the case of amantadine and rimantadine that developed resistance for influenza A strain. In the host cell, the drug slow and prevent the influenza to cross the border into the cell. The prodrug of oseltamivir is ethyl ester so it needs to be ester hydrolyzed. At first when administered in an inactive form, oseltamivir has no sign of effective until it gets to the liver where the drug is put into action by hydrolyzed into its active form and the release of carboxylate from oseltamivir. This is the active metabolite that inhibits influenza A and B virus neuraminidase. On the surface of the influenza virus are neuraminidase coatings that allow the virus to invade the host cell membranes and then replicates into large number inside the host cell. Once the patient is affected with influenza virus, with oseltamivir the the surface of neuraminidase is bound and prevent the virus to leave the host cell. This will restrict the virus to replicate and multiply in number, which result in the body immune system a higher chance to kill the virus.
REFERENCES:
[1] http://www.niaid.nih.gov/topics/Flu/understandingFlu/Pages/overview.aspx/ (accessed January 29, 2014).
[2] Engel, D. A., The influenza virus NS1 protein as a therapeutic target. Antiviral Research 2013, 99, (3), 409-16.
[3] Davey, J.; Colman, A.; Dimmock, N. J., Locaton of influenza virus M, NP, and NS1 proteins in microinjected cells. J. gen. Virol. 1985, 66, (11), 2319-34.
[4] Hale, B. G.; Randall, R.. E.; Dimmock, Ortin. J.; Jackson, D., The multifunctional NS1 protein of influenza A viruses. J. gen. Virol. 2008, 89, (10), 2359-76.